There are about 6.3 million fractures in the United States annually and closed fractures constitute a vast majority of these fractures. There are roughly 1,000,000 patients who have skeletal defects each year in the United States that require bone graft procedures to achieve union. These include applications arising from resection of primary and metastatic tumors, bone loss after skeletal trauma, primary and revision total joint arthroplasty with bone deficiency, spinal arthrodesis, and trabecular voids following osteoporotic insufficiency fractures. Bone grafts are also required to fill voids in metaphyseal bone fractures which include the distal radius, tibial plateau, proximal femur, and calcaneous fractures. Bone grafts are also used in other orthopedic applications such as being used as a bone fixative, as a suture reinforcement, and as scaffolds for guided regeneration of the alveolar bone in dentistry and reconstruction of mandibula, femoral neck osteonecrosis, and fusion of spinal processes.
Current clinical methods of treating skeletal defects involve bone transplantation or the use of other materials to restore continuity. Autologous bone graft has generally been the preferred bone replacement method because it provides osteogenic cells, osteoinductive factors, and an osteoconductive matrix for healing. However, the limited supply of autograft bone and donor site morbidity both restrict its use.
Allograft bone, although available in abundant supply, has drawbacks that include reduced rates of graft incorporation compared to autograft bone, and the possibility of pathogen transfer from donor to host.
Metals provide immediate mechanical support at the defect site but exhibit less than ideal overall integration with host tissue and can eventually fail due to fatigue loading if the bone does not heal prior to fatigue failure of the metal.
Ceramics, such as β-tricalcium phosphate (β-TCP) and hydroxyapatite (HA) are both osteoconductive, and have found clinical use as surface coatings on metal prostheses to enhance bonding to bone. In particulate form, they offer increased mechanical strength to polymeric composite materials primarily in compression, but are less effective in enhancing resistance to torsional and bending forces.
Polymethyl methacrylate (PMMA) bone cement can be injected or molded and is sometimes used to fill both cavitary and segmental defects, such as those that result from the curettage of a giant cell tumor or from the resection of a vertebral body in metastatic disease, respectively. However, the bone cement undergoes an exothermic polymerization reaction during implantation and can release a substantial amount of heat that risks local tissue injury. Additionally, PMMA is non-biodegradable and can thus accumulate fatigue damage with time and eventually undergo mechanical failure.
The use of polyhyroxyalkanonates such as homopolymers of poly(L-lactic acid) (PLLA), poly(glycolic acid) (PGA), polycaprolactone (PCL), poly(trimethylene carbonate), poly(butylene terephthalate), poly(hydroxybutyrate), poly(hydroxyvalerate), and poly(dioxanone) (PDS) and their copolymers is limited to rigid preformed devices. A group of photopolymerizable poly(anhydrides) consisting of polymers of sebacic acid (SA) alone, or copolymers of SA with either 1,3-bis(p-carboxyphenoxy) propane, or 1,6-bis(p-carboxyphenoxy) hexane (CPH) have been developed for orthopedic applications as scaffolds but ultraviolet light is typically required in the crosslinking step which can limit their use to shallow skeletal defects.
Poly(propylene fumarate) polymers have been developed for orthopedic applications but their degradation rate is very slow taking more than a year to degrade. Poly(caprolactone fumarate) polymers have also been developed to improve degradibility and injectibility compared to poly(propylene fumarate). However, poly(caprolactone) has significantly lower mechanical strength in compression compared to poly(propylene fumarate).
In addition to hard skeletal tissue fractures and defects, many people also suffer from soft skeletal tissue injuries, such as injuries or defects to cartilage. For instance, an estimated 43 million Americans are affected by arthritis, a condition associated with degeneration of the involved joint surfaces, and one million patients every year undergo surgery for osteoarthritis of their knees, hips, shoulders and spine. In addition to joint space narrowing, the degenerative articular cartilage changes often are associated with peripheral joint osteophytosis, subchondral bone sclerosis, and cystic bony changes.
Cartilage provides a smooth, near frictionless articulating surface and acts as a mediator for load transfer to the underlying subchondral bone. The regenerative capacity of damaged articular cartilage is limited compared with other musculoskeletal tissues such as bone and muscle. Mature articular cartilage has a limited potential for the repair of critical-sized defects because of its avascularity and the absence of stem cells. Cartilage defects can be due to traumatic injury, congenital abnormality, degenerative diseases (osteoarthritis) or can be age related.
Methods of treatment used for cartilage defects in the last three decades include lavage and debridement, penetration of the subchondral bone by arthroscopic abrasion, drilling, or microfracture techniques, altering joint loading, perichondrial or periosteal transplants, chondrocyte or mesenchymal stem cell transplant, treatment with growth factors, mechanical loading, joint osteotomy, and total joint replacement. There are many disadvantages of these procedures. These procedures show only temporary positive outcomes, can cause donor site morbidity, involve pathogen transfer for allograft procedures, show reduced biological activity in the grafts for elderly patients, have unfavorable long-term clinical outcomes, and are highly invasive. Furthermore, the success of the treatment depends on the severity of injury and age of the patient. Small defects heal more quickly than larger defects and articular injuries heal more quickly in children than in adults.
In view of the above, a need currently exists for biomedical compositions and methods of repairing skeletal tissue. In particular, a need currently exists for a biomedical composition that may be used for skeletal tissue support and/or regeneration that cannot only be used to treat hard skeletal tissue but also can be used to treat soft skeletal tissue.
In this regard, the present disclosure is directed to biomedical compositions that, once crosslinked, provide a polymer network for use in treating skeletal tissue. Of particular advantage, the biomedical compositions can be formulated and tailored for treating hard skeletal tissue and/or soft skeletal tissue. In one embodiment, for instance, the present disclosure is directed to a biodegradable scaffold composition that comprises a hydrogel/ceramic nanocomposite that can provide temporary structural support to regenerating skeletal tissue and can degrade concurrently with the migration of bone marrow stromal cells.
In an alternative embodiment, the present disclosure is directed to a biomedical hydrogel composition particularly well suited for treating soft skeletal tissue. Of particular advantage, the hydrogel composition can be injected and hardened in-situ. Once applied, the hydrogel composition can form a matrix that can guide the organization, differentiation, proliferation and development of seeded cells into the desired tissue.